Stable lactide particles

ABSTRACT

The present invention is directed to a method for the manufacture of stable lactide particles, more specifically lactide particles which are stable enough to be stored and transported at room temperature and have a quality high enough for use as starting material for polylactic acid. The lactide particles are obtained via a flaking process, comprising the contacting of a continuous flow of molten lactide with a surface on which the lactide solidifies and subsequently is removed from said surface.

The present invention relates to lactide particles, more specifically tolactide particles which are stable enough to be stored and transportedat room temperature and which have a quality high enough for use asstarting material for polylactic acid.

The continued depletion of landfill space, the depletion of the fossilenergy reserves, in particular of oil, the subsequent need to usetherefore and in relation to various greenhouse gas related issues, newcarbon form renewable resources, and the problems associated withincineration of waste, have led to the need for development of trulybiodegradable polymers to be utilized as substitutes fornon-biodegradable or partially biodegradable, petrochemical-basedpolymers in packaging, paper coating and other non-medical industryapplications, hereinafter referred to as bulk applications. The use oflactic acid and lactide to manufacture a biodegradable polymer is wellknown in the medical industry. As disclosed by Nieuwenhuis et al. (U.S.Pat. No. 5,053,485), such polymers have been used for makingbiodegradable sutures, clamps, bone plates and biologically activecontrolled release devices. It will be appreciated that processesdeveloped for the manufacture of polymers to be utilized in the medicalindustry have incorporated techniques that respond to the need for highpurity and biocompatibility in the final polymer product.

Furthermore, the processes were designed to produce small volumes ofhigh dollar-value products, with less emphasis on manufacturing cost andyield.

It is known that lactic acid undergoes a condensation reaction to formpolylactic acid upon dehydration. Dorough recognized and disclosed inU.S. Pat. No. 1,995,970, that the resulting polylactic acid is limitedto a low molecular weight polymer of limited value, based on physicalproperties, due to a competing depolymerization reaction in which thecyclic dimer of lactic acid, lactide, is generated. As the polylacticacid chain lengthens, the polymerization reaction rate decelerates untilit reaches the rate of the depolymerization reaction, which effectively,limits the molecular weight of the resulting polycondensation polymers.

Therefore, in most publications, processes for the production forpolylactic acid are described wherein from lactic acid first aprepolymer is prepared, said prepolymer is depolymerised in the presenceof a catalyst to form crude lactide by a ring-closure reaction, saidcrude lactide is subsequently purified and lactide is used as startingmaterial for the preparation of polylactic acid by ring-openingpolymerization. For the purpose of this description the term polylacticacid and polylactide are used interchangeably.

It is well known that lactic acid exists in two forms which are opticalenantiomers, designated as D-lactic acid and L-lactic acid. EitherD-lactic acid, L-lactic acid, or mixtures thereof may be polymerized toform an intermediate molecular weight polylactic acid which, after thering-closure reaction, generates lactide as earlier disclosed. Thelactide (sometimes also referred to as dilactide), or the cyclic dimerof lactic acid, may have one of three types of stereochemicalconfigurations depending on whether it is derived from two L-lactic acidmolecules, two D-lactic acid molecules or an L-lactic acid molecule anda D-lactic acid molecule. These three dimers are designated L-lactide,D-lactide, and meso-lactide, respectively. In addition, a 50/50 mixtureof L-lactide and D-lactide with a melting point of about 126° C. isoften referred to in the literature as D,L-lactide. The optical activityof either lactic acid or lactide is known to alter under certainconditions, with a tendency toward equilibrium at optical inactivity,where equal amounts of the D and L enantiomers are present. Relativeconcentrations of D and L enantiomers in the starting materials, thepresence of impurities or catalysts, varying temperatures, residencetimes, and pressures are known to affect the rate of such racemization.The optical purity of the lactic acid or the lactide is decisive for thestereochemistry of the polylactic acid obtained upon ring-openingpolymerization of the lactide. With respect to polylactic acid,stereochemistry, and molecular weight are the key parameters for polymerquality.

When preparing polylactic acid for the medical industry oftencrystalline powdery lactide is used as the starting material. Thesecrystals, which are commercially available for over 30 years now, arehighly hygroscopic and are packed under inert atmosphere in damp- andair-tight packages and stored in freezers (temperature below 12° C.). Itwill be clear that these precautions cannot be taken when polylacticacid is used for bulk applications because it would render the producttoo expensive.

In publications describing processes for the preparation of polylacticacid for bulk applications, the lactide formed and purified is directlyfed in its molten, liquid form to a polymerization reactor to formpolylactide. See for instance EP 0,623,153 and U.S. Pat. No. 6,875,839.By the direct conversion of the freshly prepared lactide to polylacticacid, the negative effects of the relative instability of lactide can becontrolled by minimizing the residence time of the lactide in thereactor. However, this process requires that the lactide production andpolylactic acid production are combined. This makes the process ratherinflexible and creates an entrance barrier for new polylactic acidproducers, because it requires large investments in equipment. Secondly,as the quality of the lactide is decisive for the molecular weight andstereo-chemistry that can be obtained in the polylactic acid, and thering-closure process and purification require strict control of thetemperature, pressure and residence time, it is also the most delicatepart of the polylactic acid production process. The risk of failure inthis part of the process enlarges the entrance barrier even more. If newpolylactic acid producers for bulk applications could simply be providedwith stable, high-quality lactide, this burden would be taken from themand substitution of petrochemical-based polymers with lactic acid-based(co)polymers could actually take place. It has been suggested totransport lactide in its molten form (melting point of D-lactide andL-lactide is 97° C.). Beside the fact that this type of transport isexpensive, the transport and storage of lactide in molten state is alsodetrimental to the quality of the lactide because racemization,hydrolysis, and polymerization reactions are accelerated at thesetemperatures. The same problem occurs in the direct conversion processwhen the residence time of the lactide is not precisely controlled.

To this end the present invention is directed to a method for themanufacture of stable, high-quality lactide particles, said methodcomprising subjecting molten lactide to a flaking process thateffectively transforms the liquid lactide melt to a coarse solidgranulate. We have found that lactide particles, also referred to asflakes, produced via the flaking process according to the presentinvention are stable enough, in terms of chemically stable againstoccurrence of racemization, oxidation and hydrolysis, for storage andtransport at ambient temperature and can readily be used as startingmaterial for the production of polylactic acid for bulk applications.

Further, it was found that the flaking method or process according tothe present invention is a rapid, cheap and surprisingly efficientmethod for producing stable lactide particles. The powdery crystallinelactides used in the medical industry are known to be manufactured viasolvent crystallization as this is a technique with which the highchemical purity, that is required in medical applications, can beachieved. Solvent crystallization is however a very expensive, notenvironmentally friendly and a complex process due to the solvents thatare used. The flaking process according to the present invention doesnot have these disadvantages.

The present flaking process does also not include lengthy processingtimes and additional extensive drying steps as is the case in forexample when a prilling process is used to manufacture lactideparticles. And further, problems such as racemization, hydrolysis andoxidation are prevented in using the flaking process according to thepresent invention, which therefore results in lactide particles of highquality, significantly higher than for example lactide particles madevia prilling.

With the flaking process according to the present invention for example,a production rate could be obtained, depending on cooling temperatureand drum rotational speed, which was minimally two to three times highercompared to an alternative process used for making lactide pastilles.

Furthermore, the resulting lactide flakes exhibit favorable propertiesmaking them very suitable for further processing. We found for examplethat the lactide flakes of the present invention can be relativelyrapidly and easy processed further in a subsequent melting step leadingto short residence times in this melting step. These short residencetimes offer the advantage that the risk of side reactions occurring,leading to for example the formation of lactic acid, lactoyllactic acidand water, is significantly reduced and thus the purity of the highquality lactide is preserved. In combination with the short residencetimes required, the temperature of the melting process can be loweredwhich also is positive as above-mentioned side reactions are less likelyto occur. Further, the lactide particles made via the present flakingprocess are easy to disperse and thus less mechanical input is requiredfor said homogenization process. This also reduces the risk of any sidereactions occurring.

The lactide used in the flaking process according to the presentinvention is in the molten form, meaning that all lactide entering thesolidification process is at a temperature above the melting point ofthe lactide. The flaking process comprises contacting a continuous flowof molten lactide with a surface with a temperature lower than themelting point of the lactide, allowing the lactide melt to solidify onsaid surface, and removing the solid lactide from that surface. Saidsurface may be cooled internally or externally and this can be done byvarious means as known to the skilled person.

In a preferred embodiment, the solidified lactide falls off of thesurface under the influence of gravity and is thus removed from thesurface.

In another preferred embodiment of the present invention, the solidifiedlactide on the surface is brought in contact with a means that removesor scrapes off the solidified lactide from said surface for productcollection.

The apparatus used for the flaking process, or at least those parts thatwill be in contact with the lactide, preferably are prepared fromcorrosion-resistant material such as stainless steel. Further, to avoidwater uptake of the lactide particles, the flaking process is preferablyconducted under inert gas or dry atmosphere such as under nitrogen ordry air.

The flaking process according to the present invention may be performedwith the conventional drum flaker apparatus used in the various thermalprocesses in chemical and food industries. With said drum flaker, moltenlactide solidifies on the surface of the drum, after which it is removedfrom said surface either by means of gravity or by means of some type ofscraping-device.

Various types of drum flakers are possible. Some examples hereof arerotating drum flakers wherein the rotating drum runs through a lactidemelt in a dip pan underneath the drum, or rotating drum flakers whereinthe lactide melt is “spread” over the rotating drum by means of forexample an overhead applicator roll. It is of course also possible toapply the lactide melt on said rotating drum by other means well-knownto the person skilled in the art. An example may be the spraying ordripping of lactide melt onto the surface of the drum.

Another example of a suited means for use in the flaking process is abelt flaker. Here the lactide melt can be applied on a cooled and movingbelt instead of a rotating drum. The lactide solidifies after which itis removed either by means of gravity or by means of some type ofscraping device.

Optionally a sieving step may be performed after the flaking process toavoid dusting during transport and during further processing to formpolylactide.

Stable lactide particles can be made having a various surface area perunit of volume. Particles can be obtained with a surface area per unitof volume of between 1000 to 3000 m⁻¹ but also up to 10000 m⁻¹. It wasfound that lactide particles having a surface area per unit of volume offrom 3000 to 10000 m⁻¹ showed the most ideal chemical stability fortransport and storage and for further processing in the subsequentmelting step or other processing steps.

As mentioned-above, the optical purity of the lactide is very importantfor the stereochemistry of the polylactic acid that is obtained.Therefore, it is preferred that the lactide present in the particlesaccording to the invention contains more than 95% by weight D- orL-lactide, preferably more than 98.5% by weight D- or L-lactide, mostpreferably more than 99.5% D-or L-lactide by weight.

The water content of the lactide is also an important factor for thestability of the lactide particles. Contamination by water ultimatelyhydrolyzes the lactide to lactic acid. It was found that if the watercontent is below 200 ppm, the stability of the lactide particles whenstored at ambient temperature in airtight and vapor-tight packages isensured for several months. Preferably, the water content is below 100ppm because it further increases the stability and thus shelf life ofthe lactide. The water content of the lactide can be measured by meansof a Karl-Fisher titration as will be known by the artisan.

Also the free acid content of the lactide (either lactic acid or lactoyllactic acid) is important for the stability and quality of the lactide.The presence of lactic acid and or lactoyl lactic acid in the lactidemonomer will result in reduced rates of polymerization in the furthermanufacture of polylactic acid and in polylactic acid polymers oflimited molecular weight. If the free acid content is below 50milli-equivalents per Kg lactide (meq.Kg⁻¹) the stability of the lactideparticles when stored at ambient temperature in air-tight andvapor-tight packages is ensured for several months. Preferably, the acidcontent is below 20 meq.Kg⁻¹ because it further increases the stabilityof the lactide. More preferably the acid content is between 0 and 10meq.Kg⁻¹ and most preferably, the free acid content is less than 5meq.Kg⁻¹. The free acid content can be measured by means of titrationusing for instance sodium methylate or potassium methylate in water-freemethanol, as will be clear for the artisan. The lactide used as startingmaterial for the shaping process may have been prepared by anyconventional lactide process such as water removal from a lactic acidsolution or condensation reaction of lactate esters, followed by aring-closure reaction in a lactide reactor with the help of a catalyst.Optionally the crude lactide is further purified by for instancedistillation and/or crystallization prior to the shaping process.

The lactide reactor can be of any suitable type that is designed forheat sensitive materials. A reactor that can maintain a uniform filmthickness, such as a falling film or agitated thin-film evaporator ismost preferred, because film formation increases the rate of masstransfer. When the rate of mass transfer is increased, lactide canquickly form and vaporize, and as lactide vaporizes, more lactide isproduced as dictated by the polylactic acid/lactide equilibriumreaction. Optionally these lactide reactors are operated under reducedpressure such as between about 1 mmHg and 100 mmHg. The temperature ofthe lactide formation is kept between 150° C. and 250° C. Many suitablecatalysts are known, such as metal oxides, metal halides, metal dusts,anionic clay, and organic metal compounds derived from carboxylic acidsor the like. Normally a tin(II) catalyst is used for lactide formation.

Stabilizers may also be added to the lactide reactor in order tofacilitate lactide formation and discourage degenerative lactic acid andlactide reactions. Stabilizers, such as antioxidants, eithermanufactured or naturally occurring, can be used to reduce the number ofdegradation reactions that occur during the process of polylactic acidand lactide production. Stabilizers may also reduce the rate of lactideformation during this process. Therefore, efficient production oflactide requires proper reactor design for minimal thermal severity anda proper balance between the catalyst and any use of processstabilizers.

A variety of stabilizers may be used. The stabilizing agent may includeprimary antioxidants and/or secondary antioxidants. Primary antioxidantsare those which inhibit free radical propagation reactions, such as andnot limited to alkylidene bisphenols, alkyl phenols, aromatic amines,aromatic nitro and nitroso compounds, and quinones. To prevent formationof free radicals secondary (or preventive) antioxidants break downhydroperoxides. Some non-limiting examples of secondary antioxidantsinclude: phosphites, organic sulfides, thioethers, dithiocarbamates, anddithiophosphates. Antioxidants include such compounds as trialkylphosphites, mixed alkyl/aryl phosphites, alkylated aryl phosphites,sterically hindered aryl phosphites, aliphatic spirocyclic phosphites,sterically hindered phenyl spirocyclics, sterically hinderedbisphosphonites, hydroxyphenyl propionates, hydroxy benzyls, alkylidenebisphenols, alkyl phenols, aromatic amines, thioethers, hindered amines,hydroquinones, and mixtures thereof. Preferably, phosphite-containingcompounds, hindered phenolic compounds, or other phenolic compounds areused as process stabilizing antioxidants. Most preferably,phosphite-containing compounds are used. The amount of processstabilizer used can vary depending upon the optical purity desired ofthe resulting lactide, the amount and type of catalyst used, and theconditions inside of the lactide reactor. Normally amounts varying from0.01 to 0.3 wt. % process stabilizer can be used.

Next to stabilizers also dehydration or anti-hydrolysis agents may beused. These dehydration agents favor the formation of lactide. Further,they may be used in a later stage of the manufacturing process forpolylactic acid as well as for preventing chain scission by water.Compounds based on peroxide may be used for this purpose but preferredare compounds containing the carbodiimide functionality. Thecarbodiimide compound is a compound having one or more carbodiimidegroups in a molecule and also includes a polycarbodiimide compound. As amonocarbodiimide compound included in the carbodiimide compounds,dicyclohexyl carbodiimide, diisopropyl carbodiimide, dimethylcarbodiimide, diisobutyl carbodiimide, dioctyl carbodiimide, diphenylcarbodiimide, naphthyl carbodiimide, etc. may be exemplified. Inparticular industrially easily available compounds such as dicyclohexylcarbodiimide, diisopropyl carbodiimide or products like Stabaxol® byRheinchemie are used.

It is also possible to add above-mentioned process stabilizers anddehydration agents to the lactide at a later stage, such as for instanceprior to the flaking and/or after the flaking step. If the stabilizersare added to the lactide after flaking, the stabilizers may be sprayedor coated onto the lactide flakes.

We have further found that the presence of the above-mentioned processstabilizers and dehydration agents also increases the stability of thelactide particles during storage.

It is of course desired to have as little as possible material such asprocess stabilizers and dehydration agents present in the lactideparticles other than lactide. Therefore, the lactide particle usuallycomprises more than 95% by weight lactide, preferably more than 98.5% byweight lactide, most preferably more than 99.5% by weight.

Depending on the lactide preparation and/or purification method theflaking process according to the present invention can either becombined with the preparation and/or purification, or not. For instance,if the lactide is obtained form distillation, it makes sense to directlycouple a flaking machine to the distillation column because the lactideis already in its melted form. Also, if the final purification step ofthe lactide comprises melt-crystallization, a flaking machine can bedirectly coupled to the melt crystallisator.

The invention is further illustrated by means of the followingnon-limiting example.

EXAMPLE Flaking of L-Lactide Using a Lab-Scale Rotating Drum Flaker.

Fresh L-lactide ex. Purac® (<5 meq/Kg free lactic acid) was molten usinga stirred, oil-heated vessel. Subsequently, the liquid with atemperature of between 105-120° C. was metered during flaking into thedip pan underneath a rotating drum flaker having a surface area of 0.75m². The liquid lactide was dosed at such a rate that the level of theliquid remained constant in the dip pan.

Due to the internal cooling of the drum, the lactide solidifies on thedrum surface. The cooling water for the rotating drum was kept at atemperature between 10 and 35° C. and the rotational speed at between 5and 15 rpm. Further, the dipping depth of the drum into the moltenlactide was varied and tests were done at a dipping depth of 20 mm and50 mm.

The flakes produced have an average height of between 0.3 and 0.7 mm, awidth of 1 to 3 mm and a length of 3 to 10 mm. The surface area per unitof volume varied between 4000 and 10000 m⁻¹. The bulk density wasbetween 500 and 600 kg/m³.

1. Method for the manufacture of stable lactide particles comprisingcontacting a continuous flow of molten lactide with a surface having atemperature lower than the melting point of the lactide, allowing thelactide melt to solidify on said surface, and subsequently removing thesolid lactide from that surface.
 2. Method according to claim 1 whereinsaid surface is cooled by external or internal means.
 3. Methodaccording to claim 1 wherein said removal is by means of contacting thesurface with the solidified lactide with a scraping device.
 4. Methodaccording to claim 1 wherein said method is carried out with a drumflaker or belt flaker.
 5. Method according to claim 1 wherein theobtained lactide particles are sieved.
 6. Stable lactide particleobtainable by the method according to claim
 1. 7. Stable lactideparticle having a surface area per unit of volume of from 1000 to 10000m⁻¹.
 8. Stable lactide particle of claim 7 having a surface area perunit of volume of from 1000 to 3000 m⁻¹.
 9. Stable lactide particle ofclaim 7 having a surface area per unit of volume of from 3000 to 10000m⁻¹.
 10. Stable lactide particle wherein the lactide particle comprisesmore than 95% by weight lactide.
 11. Stable lactide particle accordingto claim 10 wherein the lactide present in the particle contains morethan 95% by weight D-lactide.
 12. Stable lactide particle according toclaim 11 wherein the lactide present in the particle contains more than95% by weight L-lactide.
 13. Stable lactide particle wherein the watercontent is below 200 ppm.
 14. Stable lactide particle wherein the freelactic acid content is below 50 milli-equivalents per kg lactide(meg.Kg⁻¹)
 15. Stable lactide particle according to claim 10 wherein thelactide particle comprises more than 98.5% by weight lactide.
 16. Stablelactide particle according to claim 10 wherein the lactide particlecomprises more than 99.5% by weight lactide.
 17. Stable lactide particleaccording to claim 10 wherein the lactide present in the particlecontains more than 98.5% by weight D-lactide.
 18. Stable lactideparticle according to claim 10 wherein the lactide present in theparticle contains more than 99.5% D-lactide by weight.
 19. Stablelactide particle according to claim 11 wherein the lactide present inthe particle contains more than 98.5% by weight L-lactide.
 20. Stablelactide particle according to claim 11 wherein the lactide present inthe particle contains more than 99.5% by weight L-lactide.
 21. Stablelactide particle according claim 13 wherein the water content is below100 ppm.
 22. Stable lactide particle according claim 13 wherein thewater content is below 50 ppm.
 23. Stable lactide particle according toclaim 14 wherein the free lactic acid content is below 50milli-equivalents per kg lactide (meg.Kg⁻¹) below 20 meg.Kg⁻¹. 24.Stable lactide particle according to claim 14 wherein the free lacticacid content is below 50 milli-equivalents per kg lactide meg.Kg⁻¹)between 0 and 10 meq.Kg⁻¹.